Research in the pulmonary pathology laboratory has been focused upon the basic biological mechanisms through which inhaled particles cause lung disease. We have developed models of asbestosis and silicosis using rats and mice and have shown that the disease process in initiated at junctions of bronchioles and alveolar ducts. One hour of exposure to chrysotile asbestos is sufficient to cause progressive fibrogenesis at alveolar duct bifurcations. The process is initiated by a complement-dependent chemoattraction of lung macrophages to the sites of particle deposition. The central working hypothesis in our laboratory is that these macrophages synthesize and secrete an array of products which mediate the pathogenesis of lung fibrosis. Studies over the past years have shown that macrophages produce a wide array of arachidonic acid metabolites. These are potent inducers of inflammation and cell migration. Now we are focusing upon a group of cell-derived proteins collectively termed "growth factors". The growth factor which is the most potent inducer of mesenchymal cell (e.g. fibroblast and smooth muscle cell) proliferation is platelet-derived growth factor (PDGF). The most potent stimulator of extracellular matrix production by mesenchymal cells is transforming growth factor beta (TGF- beta). We have shown that lung macrophages secrete generous quantities of both of these factors. Thus, we postulate that inhalation of toxic particles activates populations of lung macrophages which produce PDGF and TGF-beta, the profibrogenic factors. We now know that along with PDGF, macrophages produce alphamacroglobulin (alpha-M), a high molecular weight antiprotease which serves as a specific binding protein for the PDGF and significantly augments its capacity to stimulate fibroblast proliferation. Also new is our finding that macrophage-derived PDGF is a potent chemotactic factor for lung fibroblasts, and this activity is enhanced by the receptor-recognized form of the alpha-M. In addition, we have shown that early passage rat lung fibroblasts exhibit high affinity receptors for both TGF-beta1 and beta-2, but the affinity is greater for beta-1 than beta-2, and this correlates with the biological activity induced by the two forms. Most interesting was the finding that TGF-beta1 acts as a powerful antagonist of the PDGF-induced mitogenesis exhibited by early passage lung fibroblasts. Ongoing studies using in situ hybridization show the expression of PDGF mRNA by lung macrophages, while other experiments are designed to block the biological activity of growth factors in vivo.